Having accomplished the research and training goals of the K99 phase, I am now prepared to transition to the ROO phase of this CDA. I have published several first-authored papers during the past two years, including my K99 project in the journal "Neurology." Consistent with the "cognitive reserve" (CR) hypothesis, the K99 results showed that lifetime intellectual enrichment lessens the negative impact of neuropathology on learning and memory in persons with multiple sclerosis (MS). I have also met my training goals, as I have acquired the MRI /fMRI analysis skills necessary for the R00 phase. As discussed in the original K99/R00 application, the primary aim of this R00 project is to use fMRI to identify the neurophysiologic basis of CR in MS. Although CR has been conceptualized as a neurophysiologic characteristic ofthe brain, research on CR has relied on behavioral / vocabulary-based estimates of CR. As such, the proposed project will provide the most direct investigation of CR in any neurologic population to date. Pilot fMRI data suggest that activity within the brain's default network (DN) is correlated with traditional vocabulary-based estimates of CR, as well as memory performance on neuropsychological tasks. Of particular note, pilot data suggest that DN activity mediates the relationship between vocabulary knowledge and memory functioning, thereby supporting the notion that DN activity represents the neurophysiologic basis of CR. Consistent with technological advances within the fMRI literature, I will use "resting state functional connectivity" to investigate the underlying functional integrity ofthe DN in persons with MS. I will investigate the correlation between a vocabulary-based estimate of CR and DN functional connectivity. I will also investigate whether the strength of DN functional connectivity mediates the relationship between vocabulary and memory functioning, which would support DN integrity as the neural basis of CR. Given the novelty of this research, a secondary aim investigating the relationship between vocabulary and DN activity in a matched group of healthy controls is necessary to charactize the specificity of the hypothesized relationship. Finally, as a tertiary aim, I will perform the first investigation ofthe neuroanatomical basis of CR in persons with MS.